The rational design of drugs to be used for chemotherapy is contingent upon (a) choosing a system which, if controlled, will have dramatic effects upon cellular function, and (b) achieving selective toxicity. The long-term objective of this proposal is to develop rational methods for control of cellular function which will demonstrate tissue and species selectivity and thus be of use in treatment of disease. Specifically, the systems which will be investigated were chosen because of their central importance in protein biosynthesis and regulation of growth control: selective modulation of these systems would be of great value to chemotherapy in general and cancer chemotherapy in particular. We shall study a number of mammalian aminoacyl-tRNA synthetases. Our objectives are (l) to develop potent and specific inhibitors of these enzymes, (2) to demonstrate the efficacy and specificity of these enzymes in vivo, (3) to ascertain if these inhibitors induce central regulatory mechanisms of growth control, and (4) to ascertain whether they have a differential effect on normal and neoplastic cells. A hypothesis is forwarded that arrest of normal mammalian cells in the Gl interval of the cell cycle is accompanied by, and perhaps triggered by, increases in intracellular uncharged/charged tRNA ratios. Experiments are proposed which will support or negate this hypothesis, and we will attempt to induce this regulatory response with the specific inhibitors of the aminoacyl-tRNA synthetases we shall design. Further, we are investigating the role of diadenosine tetraphosphate in cell growth and its possible role as mediator in the pleiotypic response; we are also investigating the biochemical mechanism of formation and destruction of this molecule.